S-6-Fluorospiro[chroman-4,4'-imidazolidine]-2',5'-dione, also named S-2,3-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dion e (U.S.A.N.: sorbinil) of the formula ##STR2## is a highly potent aldose reductase inhibitor having especial value in effectively controlling the chronic complications of diabetes mellitus. (Sarges, U.S. Pat. No. 4,130,714.)
The present invention is directed to chiral compounds of the formula ##STR3## wherein R is hydrogen or benzyloxycarbonyl and Y is hydroxy or amino, which are useful as intermediates in the synthesis of sorbinil; processes useful in the preparation of these intermediates; and processes for the conversion of these intermediates to sorbinil.
Heretofore, sorbinil was prepared by resolution of the corresponding racemic 6-fluorospiro[chroman-4,4'-imidazolidine]-2',5'-dione, of the formula ##STR4## with highly toxic brucine as the resolving agent in high volumes of solvent (Sarges, U.S. Pat. No. 4,130,714), or with (-)-3-aminomethylpinane, or (+)-3-aminomethylpinane or (-)-2-amino-2-norpinane/quinine combinations (Sysko, European Patent Application publication No. 109,231). Sorbinil has also been prepared by an alternative synthesis in which the required chirality is induced during the synthetic sequence (Sarges, U.S. Pat. No. 4,286,098).
Our recent U.S. Pat. No. 4,435,578 describes an improved process for sorbinil in which the ureido compound of the formula ##STR5## is resolved to form S-6-fluoro-4-ureidochroman-4-carboxylic acid as either its D-(+)-(1-phenethyl)amine or its L-(-)-ephedrine salt, followed by simple cyclization to sorbinil in glacial acetic acid.
Surprisingly, we have now also found that precursor 6-fluoro-4-(benzyloxycarbonylamino)-4-carboxylic acid, of the formula ##STR6## is readily resolved as its 1-(-)-alpha-methylbenzylamine salt to produce S-6-fluoro-4-(benzyloxycarbonylamino)chroman-4-carboxylic acid [of the formula (II) wherein R is benzyloxycarbonyl and Y is hydroxy]. The latter can be converted to other heretofor unavailable intermediates of the formula (II) which in turn are directly convertible to sorbinil, thus providing improved synthetic methods for this valuable medicinal agent. The racemic precursor is conveniently derived from the above racemic imidazolidine of the formula (A) via the amino acid of the formula ##STR7## In this manner, outstanding yields of sorbinil are obtained with a readily available, relatively inexpensive optically active amine. At the same time the use of a highly toxic resolving agent is avoided. The efficiency of this process is further enhanced by isolating the undesired enantiomer from mother liquors and recycling to fresh racemate, via precursor 6-fluoro-4-chromanone.